Identification of N-(5-tert-Butyl-isoxazol-3-yl)-N′-{4-[7-(2-morpholin-4-yl-ethoxy)imidazo[2,1-b][1,3]benzothiazol-2-yl]phenyl}urea Dihydrochloride (AC220), a Uniquely Potent, Selective, and Efficacious FMS-Like Tyrosine Kinase-3 (FLT3) Inhibitor

Qi, Chaorong; Sprankle, Kelly G.; Grotzfeld, Robert M.; Lai, Andiliy; Carter, Todd A.; Velasco, Anne Marie; Gunawardane, Ruwanthi N.; Cramer, Merryl; Gardner, Michael F.; James, Joyce; Zarrinkar, Patrick P.; Patel, Hitesh; Bhagwat, Shripad S.

doi:10.1021/jm9007533

Cited by 174 publications

(89 citation statements)

References 20 publications

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“…Lestaurtinib/CEP-701 (Knapper et al, 2006), which also targets the oncogenic JAK2/STAT5 signalling axis (Hexner et al, 2008); Tandutinib/MLN518 which has been shown to be highly effective in inhibiting FLT3, PDGFRb, and Kit and is progressing to Phase II clinical trials (DeAngelo et al, 2006;Shepard et al, 2012); AC220, one of the first to completely inhibit FLT3 activity ex vivo at clinically relevant doses (Chao et al, 2009;Zarrinkar et al, 2009) and also currently in Phase II trials, and KW-2449, a multi-kinase inhibitor of FLT3, Abl, Abl-T315I, and Aurora kinase (Shiotsu et al, 2009) also awaiting progression to Phase II (Pratz et al, 2009).…”

Section: Discussionmentioning

confidence: 99%

FLT3-driven redox-modulation of Ezrin regulates leukaemic cell migration

Corcoran

Cotter

2012

Free Radical Research

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Access to the full text of the published version may require a subscription. and ideas for this work, and who supported and believed in me throughout -I am grateful to have had the opportunity to learn from the best. I must also give a huge thank you to Kate Cotter, who made me feel at home from day one, and who has continued to be a tireless source of energy and assistance. RightsI was fortunate to interact with a vibrant, dynamic group in the Cotter Lab and I owe a huge thanks to every single member, past-Claire, Ruth, Carolyn, Chris, Ashley, To all the friends that I have made in U.C.C. and beyond during this process, as well as those friends lucky enough not to be involved but who still got to listen to all that whingeing-thank you! Lastly, I am most indebted to those closest to me. My mam -who is always ready to listen, comfort and reassure, and as a result probably knows more than she ever wanted to about cells and reactive oxygen species! My dad, a real scientist, who never stops teaching and never stops learning, and is still the person I turn to with my "homework" questions! I am so grateful to you both for your wisdom, encouragement and patience; truly I could not have achieved this without you. ToSinead and Dara, for all the much needed distractions and laughs, and for even being interested! And to John, for being there throughout, for the joy and the inspiration. To everyone still waiting for good news or the right medicine 'Happy is he who gets to know the reasons for things.' -Virgil DeclarationThis thesis has not been submitted in whole or in part to this or any other university for any degree and is, unless otherwise stated, the original work of the author. pathway may allow for combination therapies to be used to impede the emergence of resistance. However, the intracellular signal transduction pathway of FLT3 is relatively obscure. The objective of this study is to further elucidate this pathway, with particular focus on the redox signalling element which is thought to be involved. Signalling via reactive oxygen species is becoming increasingly recognised as a crucial aspect of physiological and pathological processes within the cell. The first part of this study examined the effects of NADPH oxidase-derived reactive oxygen species on the tyrosine phosphorylation levels of acute myeloid leukaemia cell lines. Using two-dimensional phosphotyrosine immunoblotting, a range of proteins were identified as undergoing tyrosine phosphorylation in response to iii NADPH oxidase activity. Ezrin, a cytoskeletal regulatory protein and substrate of Src kinase, was selected for further study.The next part of this study established that NADPH oxidase is subject to regulation by FLT3. Both wild type and oncogenic FLT3 signalling were shown to affect the expression of a key NADPH oxidase subunit, p22phox, and FLT3 was also demonstrated to drive intracellular reactive oxygen species production. The NADPH oxidase target protein, Ezrin, undergoes phosphorylation on two tyrosine residues downstream of FLT3 signalli...

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Section: Discussionmentioning

confidence: 99%

FLT3-driven redox-modulation of Ezrin regulates leukaemic cell migration

Corcoran

Cotter

2012

Free Radical Research

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“…AC220, a tyrosine kinase inhibitor (TKI), now known as quizartinib, is a highly potent inhibitor of FLT3 and other kinases including CSF1R, RET, PDGFR, and KIT (Pemmaraju et al 2011;Chao et al 2009). AC220 was initially identified and designed by Chao et al (Chao et al 2009) as "Compound 7," named N-(5-tert-butyl-isoxazol-3-yl ,3]benzothiazol-2-yl]phenyl}urea dihydrochloride.…”

Section: Drug Development Of Ac220 As Flt3 Inhibitormentioning

confidence: 99%

FLT3-ITD. Clinical (Sorafenib/AC220)

Cortes

Pemmaraju

2014

Targeted Therapy of Acute Myeloid Leukemia

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A plethora of new molecular abnormalities has been identified to be associated with acute myelogenous leukemia (AML). These markers have contributed to a more accurate prognostic stratification of these patients, and have nurtured hopes for effective targeted therapies. One such abnormality is the FMS-like tyrosine kinase 3, or FLT3 gene mutation, present in approximately 30 % of AML patients. The presence of the FLT3 internal tandem duplication (FLT3-ITD) confers a poorer prognosis with higher risk of relapse for this subset of AML patients. Rapid development of a large number of FLT3 tyrosine kinase inhibitors (TKIs) has enabled an exciting era of research and treatment for patients with these abnormalities. The expectation is that FLT3 inhibition may offer improvements in outcomes in this poor prognosis group of patients. Early data suggest that this promise may be materializing for patients. This chapter will focus on two of these FLT3 inhibitors, sorafenib (Nexavar®) and AC220 (quizartinib).

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“…The drug is a potent inhibitor of FLT3. However, it also shows activity against other members of the type III RTK family of kinases, but has little effect on approximately 400 other kinases [36][37][38]. It is currently being tested in phase II clinical trials [39].…”

Section: Drugs Targeting Kinasesmentioning

confidence: 99%